Antibacterial properties and clinical potential of pleuromutilins

ABSTRACT Multidrug resistance (MDR) by bacterial pathogens constitutes a global health crisis, and resistance to treatment displayed by biofilm-associated infections (e.g., cystic fibrosis, surgical sites, and medical implants) only exacerbates a problem that is already difficult to overcome. Antimicrobial peptides (AMPs) are a promising class of therapeutics that may be useful in the battle against antibiotic resistance, although certain limitations have hindered their clinical development. The goal of this study was to examine the therapeutic potential of novel AMPs derived from the multifunctional respiratory host defense protein SPLUNC1. Using standard growth inhibition and antibiofilm assays, we demonstrated that a novel structurally optimized AMP, α4-short, was highly effective against the most common group of MDR bacteria while showing broad-spectrum bactericidal and antibiofilm activities. With negligible hemolysis and toxicity to white blood cells, the new peptide also demonstrated in vivo efficacy when delivered directly into the airway in a murine model of Pseudomonas aeruginosa-induced respiratory infection. The data warrant further exploration of SPLUNC1-derived AMPs with optimized structures to assess the potential application to difficult-to-cure biofilm-associated infections. IMPORTANCE The rise of superbugs underscores the urgent need for novel antimicrobial agents. Antimicrobial peptides (AMPs) have the ability to kill superbugs regardless of resistance to traditional antibiotics. However, AMPs often display a lack of efficacy in vivo. Sequence optimization and engineering are promising but may result in increased host toxicity. We report here the optimization of a novel AMP (α4-short) derived from the multifunctional respiratory protein SPLUNC1. The AMP α4-short demonstrated broad-spectrum activity against superbugs as well as in vivo efficacy in the P. aeruginosa pneumonia model. Further exploration for clinical development is warranted.

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Cannabinoquinones: Synthesis and Biological Profile

Biomolecules ◽

10.3390/biom11070991 ◽

2021 ◽

Vol 11 (7) ◽

pp. 991

Author(s):

Diego Caprioglio ◽

Daiana Mattoteia ◽

Orazio Taglialatela-Scafati ◽

Eduardo Muñoz ◽

Giovanni Appendino

Keyword(s):

Oxidative Degradation ◽

Alkyl Substituent ◽

Systematic Investigation ◽

Clinical Development ◽

Drug Status ◽

Phase 2 ◽

Biological Profile ◽

Oxidative Dearomatization ◽

Sufficient Stability ◽

Clinical Potential

Neutral cannabinoids are oxidatively unstable and are converted into quinone derivatives by atmospheric- and/or chemical oxidative dearomatization. The study of cannabinoquinones has long been plagued by their lability toward additional oxidative degradation, but full substitution of the quinone ring, as well as the introduction of steric hindrance on the alkyl substituent, have provided sufficient stability for a systematic investigation of their bioactivity and for further clinical development. These studies culminated in the discovery of the aminocannabinoquinone VCE-004.8 (5), a compound under phase 2 clinical development with orphan drug status by EMA and FDA for the management of scleroderma. The synthesis and rich chemistry of these compounds will be described, summarizing their biological profile and clinical potential.

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Semi-synthesis as a tool for broadening the health applications of bioactive olive secoiridoids: a critical review

Natural Product Reports ◽

10.1039/d0np00084a ◽

2021 ◽

Author(s):

Manuela Oliverio ◽

Monica Nardi ◽

Maria Luisa Di Gioia ◽

Paola Costanzo ◽

Sonia Bonacci ◽

...

Keyword(s):

Critical Review ◽

Natural Compounds ◽

Effective Strategy ◽

Synthetic Analogues ◽

Health Applications ◽

Natural And Synthetic

Semi-synthesis is an effective strategy to obtain both natural and synthetic analogues of the olive secoiridoids, starting from easy accessible natural compounds.

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Characteristics of the Frequency-Following Response to Speech in Neonates and Potential Applicability in Clinical Practice: A Systematic Review

Journal of Speech Language and Hearing Research ◽

10.1044/2020_jslhr-19-00322 ◽

2020 ◽

Vol 63 (5) ◽

pp. 1618-1635

Author(s):

Céline Richard ◽

Mary Lauren Neel ◽

Arnaud Jeanvoine ◽

Sharon Mc Connell ◽

Alison Gehred ◽

...

Keyword(s):

Systematic Review ◽

Cochrane Library ◽

Neurodevelopmental Outcomes ◽

Frequency Following Response ◽

Ovid Medline ◽

Published Evidence ◽

Mesh Terms ◽

Potential Applicability ◽

Clinical Potential

Purpose We sought to critically analyze and evaluate published evidence regarding feasibility and clinical potential for predicting neurodevelopmental outcomes of the frequency-following responses (FFRs) to speech recordings in neonates (birth to 28 days). Method A systematic search of MeSH terms in the Cumulative Index to Nursing and Allied HealthLiterature, Embase, Google Scholar, Ovid Medline (R) and E-Pub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Web of Science, SCOPUS, COCHRANE Library, and ClinicalTrials.gov was performed. Manual review of all items identified in the search was performed by two independent reviewers. Articles were evaluated based on the level of methodological quality and evidence according to the RTI item bank. Results Seven articles met inclusion criteria. None of the included studies reported neurodevelopmental outcomes past 3 months of age. Quality of the evidence ranged from moderate to high. Protocol variations were frequent. Conclusions Based on this systematic review, the FFR to speech can capture both temporal and spectral acoustic features in neonates. It can accurately be recorded in a fast and easy manner at the infant's bedside. However, at this time, further studies are needed to identify and validate which FFR features could be incorporated as an addition to standard evaluation of infant sound processing evaluation in subcortico-cortical networks. This review identifies the need for further research focused on identifying specific features of the neonatal FFRs, those with predictive value for early childhood outcomes to help guide targeted early speech and hearing interventions.

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